V3 loop of human immunodeficiency virus type 1 reduces cyclin E expression and induces G1 arrest in interleukin 2-dependent T cells.
We previously described that V3 loop derived from the HTLV-III BH10 clone V3-BH10 markedly suppressed IL-2-driven T cell proliferation and produced G1 arrest of the cells. Here, we tested the effect of V3-BH10 on the molecules that are involved in transition from the G1 to S phase of the cell cycle. The effect of V3-BH10 on the IL-2-induced expression of G1 cyclins, Cdk inhibitors, and phosphorylation of retinoblastoma protein (pRb) was tested by immunoblotting, using the IL-2-dependent CD4-positive cell line Kit 225. Furthermore, IL-2-dependent kinase activity of the cyclin E-Cdk2 complex was investigated with histone H1 as a substrate. V3-BH10 reduced the IL-2-dependent expression of cyclin E, but not that of cyclin D and Cdk inhibitors such as p21 and p27. As the result of reduction of cyclin E, histone H1 kinase activity of the cyclin E-Cdk2 complex was markedly reduced even in the presence of rIL-2, followed by incomplete phosphorylation of pRb. The reduction in hyperphosphorylation of pRb by V3-BH10 led to G1 arrest of the cell cycle. Thus, V3-BH10 induced G1 arrest in IL-2-dependent cell cycle progression by reducing cyclin E expression, which may be one of the mechanisms underlying the dysfunction of T cells in HIV-1-infected people.
Sakaida
H
H
Research Center for Immunodeficiency Virus, Institute for Virus Research, Kyoto University, Japan.
Kawamata
S
S
Hattori
T
T
Uchiyama
T
T
D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D007376:Interleukin-2; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019938:Cyclin D1; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases